What are virus-like particles and how are they being used in the design of AIDS vaccine candidates?
Many vaccines teach the body how to fend off a chosen bacterium, virus or parasite by presenting it with a killed or weakened form of that pathogen.
These approaches are not, however, viable for HIV due to concerns that any such virus preparation may not be completely inactivated, or that its weakened form might mutate and regain its ability to cause disease. So scientists have relied instead on delivering purified proteins derived from recombinant HIV genes, or the genes themselves, to trigger cellular (T-cell) and antibody (B-cell) responses against HIV (see VAX July 2008 Special Issue, Understanding the Immune System and AIDS Vaccine Strategies).
AIDS researchers have tended to favor recombinant vaccines, in which parts of the pathogen are synthesized from scratch and used as immunogens (the active ingredient in the vaccine candidate). In some cases, the vaccine candidates have consisted of soluble proteins, which, as the phrase suggests, dissolve easily in water. This is the approach that was used in one vaccine candidate used in the RV144 trial (see VAX Sep. 2009 Spotlight article, First Evidence of Efficacy from Large-Scale HIV Vaccine Trial), which demonstrated modest efficacy, and the candidate used in the Step trial (see VAX Oct.-Nov. 2007 Spotlight article, A STEP Back?), which did not.
A viral imitator
Another type of recombinant vaccine that has captured the attention of scientists in recent years relies on virus-like particles (VLPs) to deliver HIV’s payload. While VLP vaccine candidates present their own challenges, these multi-protein structures have yielded impressive results in studies and represent a safe and potentially more effective alternative for HIV vaccines.
Studies suggest that VLP vaccines against the influenza virus might be able to provide more potent and longer-lasting protection than do the current seasonal vaccines. AIDS researchers are developing VLP-based vaccines as well. A variety of VLPs are currently in various stages of pre-clinical and clinical development.
So how do these candidates work? As you may know, viruses need a human host to multiply. A virus particle—or virion—is essentially a combination of DNA or RNA material packaged in a protein capsule that’s made by infected cells and spreads by budding. A number of years ago, researchers described during their study of the hepatitis B virus that it’s possible to assemble particles that lack a viral genome and some of its proteins, but can still be recognized by the immune system.
VLPs present parts of the proteins specific to the targeted pathogen, such as the Envelope (see VAX March 2011 Primer on Understanding HIV’s Envelope Protein) that sits on HIV’s surface and is used by the virus to invade cells.
VLPs are similar in size and conformation to intact virions. Because they lack crucial genetic material, they are non-infectious and so provide a safer alternative to weakened viruses. Many VLP vaccine candidates are also built from viruses that infect bacteria, or those that infect plants, animals, or even humans. Studies have found that VLP vaccine candidates can be highly immunogenic, in part because they can display multiple antigens on their surface, improving interaction with components of the immune system and thus increasing the odds of inducing a potent antibody response.
VLPs in HIV science
AIDS vaccine researchers are employing VLPs in different ways. One group of researchers is using them to induce antibodies to a part of the protein spike that protrudes from HIV’s Envelope called the membrane proximal external region. This part of the spike is important for fusion of the viral membrane with the target cell membrane. Researchers are using a baculovirus—which infects cultured insect cells—to express the recombinant HIV genes. The VLPs are then purified from infected cells.
Researchers have also created a VLP vaccine candidate that swapped one segment of HIV’s spike—another name for the Envelope, or trimer—with a smaller protein from the influenza virus. They devised this method to try and make portions of the HIV spike more accessible to the human immune system.
Finally, researchers have developed a test that uses VLPs to screen for proteins that bind to the earliest ancestors of broadly neutralizing antibodies (bNAbs), which prevent a broad variety of HIV variants from invading cells in laboratory studies. Scientists have identified dozens of these bNAbs in people with chronic HIV, but the antibodies take years to develop. So engaging these early cells, known as germ-line precursors, represents a potential road to success in developing a vaccine candidate that might induce these coveted bNAbs (see VAX May 2013 Primer onUnderstanding How a Vaccine May be Designed to Induce Broadly Neutralizing Antibodies).
While VLP vaccine candidates are an attractive alternative, they present manufacturing challenges that developers will need to overcome. Some VLP candidates are too costly to produce in significant quantities and the biological structures of some VLPs are, in some cases, too complicated for large-scale production.
Still, there are now two recombinant vaccines on the market—one for hepatitis B and the other for human papilloma virus—that employ VLP platforms. Another VLP-based vaccine candidate, GlaxoSmithKline’s malaria vaccine candidate RTS,S, is in late-stage clinical testing (see VAX Nov. 2012 Global News).
The hope is that VLPs may help AIDS vaccine scientists achieve similar success.